Student or educator? Sign up with your school email and get 6 months of Pro free.
CoChat
Sign Up
Cited by 263

The DOI matches its Crossref record; 12 of the 12 references it cites were found in a registry or an index.

α-Synuclein expression and Nrf2 deficiency cooperate to aggravate protein aggregation, neuronal death and inflammation in early-stage Parkinson's disease

Open access
Lastres-Becker, Isabel, Ulusoy, Ayse, Innamorato, Nadia G., Sahin, Gurdal, Rábano, Alberto, Kirik, Deniz, Cuadrado, Antonio·2012·Human Molecular Genetics
DOI 10.1093/hmg/dds143
Open this paper in CoChat — free account

Abstract

Although α-synuclein (α-SYN) aggregation is a hallmark of sporadic and familial Parkinson's disease (PD), it is not known how it contributes to early events of PD pathogenesis such as oxidative and inflammatory stress. Here, we addressed this question in a new animal model based on stereotaxic delivery of an adeno-associated viral vector (rAAV) for expression of human α-SYN in the ventral midbrain of mice lacking the transcription factor Nrf2 (Nrf2(-/-)). Two months after surgery, Nrf2(-/-) mice exhibited exacerbated degeneration of nigral dopaminergic neurons and increased dystrophic dendrites, reminiscent of Lewy neurites, which correlated with impaired proteasome gene expression and activity. Dopaminergic neuron loss was associated with an increase in neuroinflammation and gliosis that were intensified in Nrf2(-/-) mice. In response to exogenously added α-SYN, Nrf2(-/-) microglia failed to activate the expression of two anti-inflammatory genes, heme oxygenase-1 (HO-1) and nicotinamide adenine dinucleotide phosphate quinone oxidorreductase-1 (NQO1). This impaired Nrf2 response correlated with a shift in the microglial activation profile, towards increased production of proinflammatory markers, IL-6, IL-1β and iNOS and reduced phagocytic capacity of fluorescent beads, and lower messenger RNA levels for TAM receptors Axl and Mer. Postmortem brain tissue samples from patients in early- to middle-stage progression of PD showed increased HO-1 expression in astrocytes and microglia, suggesting an attempt of the diseased brain to compensate these hallmarks of PD through activation of the Nrf2 pathway. This study demonstrates that α-SYN and Nrf2 deficiency cooperate on protein aggregation, neuroinflammation and neuronal death and provides a bifactorial animal model to study early-stage PD.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1093/hmg/dds143

Cites

12 of 12 references verified0 citation errors · 0 not checkable

Statistics

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Show all 12 references

Research works printed but not linked: 56

  1. Hardy, 2010, Genetic analysis of pathways to Parkinson disease, Neuron, 68, 201, 10.1016/j.neuron.2010.10.014 · DOI · Paper page
  2. Lotharius, 2002, Impaired dopamine storage resulting from alpha-synuclein mutations may contribute to the pathogenesis of Parkinson's disease, Hum. Mol. Genet., 11, 2395, 10.1093/hmg/11.20.2395 · DOI · Paper page
  3. Outeiro, 2009, Dopamine-induced conformational changes in alpha-synuclein, PLoS ONE, 4, e6906, 10.1371/journal.pone.0006906 · DOI
  4. Bisaglia, 2010, Dopamine quinones interact with alpha-synuclein to form unstructured adducts, Biochem. Biophys. Res. Commun., 394, 424, 10.1016/j.bbrc.2010.03.044 · DOI
  5. Lee, 2009, Neuroinflammation in Parkinson's disease, J. Neuroimmune Pharmacol., 4, 419, 10.1007/s11481-009-9176-0 · DOI · Paper page
  6. Halliday, 2011, Glia: initiators and progressors of pathology in Parkinson's disease, Mov. Disord., 26, 6, 10.1002/mds.23455 · DOI · Paper page
  7. Austin, 2006, Alpha-synuclein expression modulates microglial activation phenotype, J. Neurosci., 26, 10558, 10.1523/JNEUROSCI.1799-06.2006 · DOI
  8. Meredith, 2008, Animal models of Parkinson's disease progression, Acta Neuropathol., 115, 385, 10.1007/s00401-008-0350-x · DOI · Paper page
  9. Eslamboli, 2005, Assessment of GDNF in primate models of Parkinson's disease: comparison with human studies, Rev. Neurosci., 16, 303, 10.1515/REVNEURO.2005.16.4.303 · DOI
  10. Georgievska, 2002, Neuroprotection in the rat Parkinson model by intrastriatal GDNF gene transfer using a lentiviral vector, Neuroreport, 13, 75, 10.1097/00001756-200201210-00019 · DOI
  11. Kirik, 2001, Delayed infusion of GDNF promotes recovery of motor function in the partial lesion model of Parkinson's disease, Eur. J. Neurosci., 13, 1589, 10.1046/j.0953-816x.2001.01534.x · DOI
  12. Decressac, 2011, GDNF fails to exert neuroprotection in a rat {alpha}-synuclein model of Parkinson's disease, Brain, 134, 2302, 10.1093/brain/awr149 · DOI · Paper page
  13. Lo Bianco, 2004, Lentiviral nigral delivery of GDNF does not prevent neurodegeneration in a genetic rat model of Parkinson's disease, Neurobiol. Dis., 17, 283, 10.1016/j.nbd.2004.06.008 · DOI
  14. Kirik, 2002, Reversal of motor impairments in parkinsonian rats by continuous intrastriatal delivery of l-DOPA using rAAV-mediated gene transfer, Proc. Natl Acad. Sci. USA, 99, 4708, 10.1073/pnas.062047599 · DOI
  15. Ulusoy, 2010, Viral vector-mediated overexpression of alpha-synuclein as a progressive model of Parkinson's disease, Prog. Brain. Res., 184, 89, 10.1016/S0079-6123(10)84005-1 · DOI
  16. Kirik, 2003, Nigrostriatal alpha-synucleinopathy induced by viral vector-mediated overexpression of human alpha-synuclein: a new primate model of Parkinson's disease, Proc. Natl Acad. Sci. USA, 100, 2884, 10.1073/pnas.0536383100 · DOI · Paper page
  17. Galvin, 1999, Axon pathology in Parkinson's disease and Lewy body dementia hippocampus contains alpha-, beta-, and gamma-synuclein, Proc. Natl Acad. Sci. USA, 96, 13450, 10.1073/pnas.96.23.13450 · DOI · Paper page
  18. St Martin, 2007, Dopaminergic neuron loss and up-regulation of chaperone protein mRNA induced by targeted over-expression of alpha-synuclein in mouse Substantia nigra, J. Neurochem., 100, 1449, 10.1111/j.1471-4159.2006.04310.x · DOI · Paper page
  19. Innamorato, 2008, The transcription factor Nrf2 is a therapeutic target against brain inflammation, J. Immunol., 181, 680, 10.4049/jimmunol.181.1.680 · DOI · Paper page
  20. Rojo, 2010, Nrf2 regulates microglial dynamics and neuroinflammation in experimental Parkinson's disease, Glia, 58, 588, 10.1002/glia.20947 · DOI · Paper page
  21. Jazwa, 2011, Pharmacological targeting of the transcription factor Nrf2 at the basal ganglia provides disease modifying therapy for experimental parkinsonism, Antioxid. Redox Signal, 14, 2347, 10.1089/ars.2010.3731 · DOI · Paper page
  22. Barone, 2011, Genetic activation of Nrf2 signaling is sufficient to ameliorate neurodegenerative phenotypes in a Drosophila model of Parkinson's disease, Dis. Model. Mech., 4, 701, 10.1242/dmm.007575 · DOI
  23. Innamorato, 2009, Role of microglial redox balance in modulation of neuroinflammation, Curr. Opin. Neurol., 22, 308, 10.1097/WCO.0b013e32832a3225 · DOI
  24. Kwak, 2007, Role of increased expression of the proteasome in the protective effects of sulforaphane against hydrogen peroxide-mediated cytotoxicity in murine neuroblastoma cells, Free Radic. Biol. Med., 43, 809, 10.1016/j.freeradbiomed.2007.05.029 · DOI
  25. Pickering, 2012, Nrf2 dependent induction of proteasome and Pa28alphabeta regulator is required for adaptation to oxidative stress, J. Biol. Chem., 287, 10021, 10.1074/jbc.M111.277145 · DOI · Paper page
  26. Ramsey, 2007, Expression of Nrf2 in neurodegenerative diseases, J. Neuropathol. Exp. Neurol., 66, 75, 10.1097/nen.0b013e31802d6da9 · DOI · Paper page
  27. von Otter, 2010, Association of Nrf2-encoding NFE2L2 haplotypes with Parkinson's disease, BMC Med. Genet., 11, 36, 10.1186/1471-2350-11-36 · DOI
  28. von Otter, 2010, Nrf2-encoding NFE2L2 haplotypes influence disease progression but not risk in Alzheimer's disease and age-related cataract, Mech. Ageing Dev., 131, 105, 10.1016/j.mad.2009.12.007 · DOI
  29. Suh, 2004, Decline in transcriptional activity of Nrf2 causes age-related loss of glutathione synthesis, which is reversible with lipoic acid, Proc. Natl Acad. Sci. USA, 101, 3381, 10.1073/pnas.0400282101 · DOI · Paper page
  30. Maingay, 2006, Ventral tegmental area dopamine neurons are resistant to human mutant alpha-synuclein overexpression, Neurobiol. Dis., 23, 522, 10.1016/j.nbd.2006.04.007 · DOI
  31. Kirik, 2003, Modeling CNS neurodegeneration by overexpression of disease-causing proteins using viral vectors, Trends Neurosci., 26, 386, 10.1016/S0166-2236(03)00164-4 · DOI
  32. Kirik, 2002, Parkinson-like neurodegeneration induced by targeted overexpression of alpha-synuclein in the nigrostriatal system, J. Neurosci., 22, 2780, 10.1523/JNEUROSCI.22-07-02780.2002 · DOI · Paper page
  33. Grealish, 2010, Characterisation of behavioural and neurodegenerative changes induced by intranigral 6-hydroxydopamine lesions in a mouse model of Parkinson's disease, Eur. J. Neurosci., 31, 2266, 10.1111/j.1460-9568.2010.07265.x · DOI
  34. Lee, 2008, Sprouting of dopamine terminals and altered dopamine release and uptake in parkinsonian dyskinaesia, Brain, 131, 1574, 10.1093/brain/awn085 · DOI
  35. Perovic, 2005, Increase of GAP-43 in the rat cerebellum following unilateral striatal 6-OHDA lesion, Synapse, 56, 170, 10.1002/syn.20142 · DOI
  36. Yamamoto, 2007, Proteasome inhibition induces glutathione synthesis and protects cells from oxidative stress: relevance to Parkinson disease, J. Biol. Chem., 282, 4364, 10.1074/jbc.M603712200 · DOI
  37. Ghee, 2000, Rat alpha-synuclein interacts with Tat binding protein 1, a component of the 26S proteasomal complex, J. Neurochem., 75, 2221, 10.1046/j.1471-4159.2000.0752221.x · DOI
  38. Bukhatwa, 2010, A comparison of changes in proteasomal subunit expression in the Substantia nigra in Parkinson's disease, multiple system atrophy and progressive supranuclear palsy, Brain Res., 1326, 174, 10.1016/j.brainres.2010.02.045 · DOI
  39. Schell, 2009, Nuclear and neuritic distribution of serine-129 phosphorylated alpha-synuclein in transgenic mice, Neuroscience, 160, 796, 10.1016/j.neuroscience.2009.03.002 · DOI
  40. Chau, 2009, Relationship between alpha synuclein phosphorylation, proteasomal inhibition and cell death: relevance to Parkinson's disease pathogenesis, J. Neurochem., 110, 1005, 10.1111/j.1471-4159.2009.06191.x · DOI
  41. Racchetti, 2012, Astrocyte stellation, a process dependent on Rac1 is sustained by the regulated exocytosis of enlargeosomes, Glia, 60, 465, 10.1002/glia.22280 · DOI
  42. McNaught, 2003, Altered proteasomal function in sporadic Parkinson's disease, Exp. Neurol., 179, 38, 10.1006/exnr.2002.8050 · DOI · Paper page
  43. Nakamura, 2006, Nuclear localization of the 20S proteasome subunit in Parkinson's disease, Neurosci. Lett., 406, 43, 10.1016/j.neulet.2006.07.050 · doi:10.1016/j.neulet.2006.07.050
  44. McNaught, 2010, The pattern of neuronal loss and survival may reflect differential expression of proteasome activators in Parkinson's disease, Synapse, 64, 241, 10.1002/syn.20719 · DOI
  45. Hu, 2006, Identification of Nrf2-regulated genes induced by chemopreventive isothiocyanate PEITC by oligonucleotide microarray, Life Sci., 79, 1944, 10.1016/j.lfs.2006.06.019 · DOI
  46. Hu, 2006, Gene expression profiles induced by cancer chemopreventive isothiocyanate sulforaphane in the liver of C57BL/6J mice and C57BL/6J/Nrf2 (−/−) mice, Cancer Lett., 243, 170, 10.1016/j.canlet.2005.11.050 · DOI · Paper page
  47. Terada, 2003, Glial involvement in diffuse Lewy body disease, Acta Neuropathol., 105, 163, 10.1007/s00401-002-0622-9 · DOI
  48. Park, 2008, Microglial phagocytosis is enhanced by monomeric alpha-synuclein, not aggregated alpha-synuclein: implications for Parkinson's disease, Glia, 56, 1215, 10.1002/glia.20691 · DOI
  49. Suganuma, 2011, Stimulation of phagocytosis by sulforaphane, Biochem. Biophys. Res. Commun., 405, 146, 10.1016/j.bbrc.2011.01.025 · doi:10.1016/j.bbrc.2011.01.025
  50. Binder, 2009, TAM receptor signalling and demyelination, Neurosignals, 17, 277, 10.1159/000231894 · DOI
  51. Zhang, 2007, Microglial PHOX and Mac-1 are essential to the enhanced dopaminergic neurodegeneration elicited by A30P and A53T mutant alpha-synuclein, Glia, 55, 1178, 10.1002/glia.20532 · DOI · Paper page
  52. Innamorato, 2010, Different susceptibility to the Parkinson's toxin MPTP in mice lacking the redox master regulator Nrf2 or its target gene heme oxygenase-1, PLoS ONE, 5, e11838, 10.1371/journal.pone.0011838 · DOI
  53. Schipper, 1998, Neural heme oxygenase-1 expression in idiopathic Parkinson's disease, Exp. Neurol., 150, 60, 10.1006/exnr.1997.6752 · DOI · Paper page
  54. Paxinos, 2004, The mouse brain in stereotaxic coordinates
  55. Schmitz, 2007, Design-based stereology in brain aging research, 10.1201/9781420005523.sec2 · DOI
  56. Gundersen, 1987, The efficiency of systematic sampling in stereology and its prediction, J. Microsc., 147, 229, 10.1111/j.1365-2818.1987.tb02837.x · DOI · Paper page

Cited by

See all 263

Metadata

Authors
Lastres-Becker, I., Ulusoy, A., Innamorato, N. G., Sahin, G., Rábano, A., Kirik, D., & Cuadrado, A.
Venue
Human Molecular Genetics
Publisher
Oxford University Press (OUP)
Published
2012-04-18
Volume
21
Issue
14
Pages
3173-3192
ISSN
  • 0964-6906 (ISSN-L)
  • 1460-2083
DOI
10.1093/hmg/dds143
OpenAlex
W2151725579
Cited by
263
References
12
FWCI
8.79
Type
journal article
Language
en
Open access
green

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

How to cite

Cite CoChat for the checks on this page, and the paper for its own findings.

This page
CoChat. (2026). Citation check: α-Synuclein expression and Nrf2 deficiency cooperate to aggravate protein aggregation, neuronal death and inflammation in early-stage Parkinson's disease. https://app.cochat.ai/papers/10.1093/hmg/dds143
The paper
Lastres-Becker, I., Ulusoy, A., Innamorato, N. G., Sahin, G., Rábano, A., Kirik, D., & Cuadrado, A. (2012). α-Synuclein expression and Nrf2 deficiency cooperate to aggravate protein aggregation, neuronal death and inflammation in early-stage Parkinson's disease. Human Molecular Genetics. https://doi.org/10.1093/hmg/dds143

Data sources

Bibliographic data: Semantic Scholar, OpenAlex, Crossref.

Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).

Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.